α-aminoketone derivatives

ABSTRACT

Alpha-aminoketone derivatives of the present invention strongly inhibit thiol protease such as papain, cathepsin B, cathepsin H, cathepsin L and calpain or the like and have excellent properties in absorbance on oral administration, tissue distribution and cell membrane permeability. The alpha-aminoketone derivatives can thus be used as therapeutic agents for treating muscular dystrophy, amyotrophy, cardiac infarction, stroke, Alzheimer&#39;s disease, disturbance of consciousness or dyskinesia caused upon brain trauma, multiple sclerosis, peripheral nervous neuropathy, cataract, inflammation, allergosis, fulminant hepatitis, osteoporosis, hypercalcemia, breast carcinoma, prostatic carcinoma or prostatomegaly. They may also be used as therapeutic agents for suppressing growth of cancer cells, preventing metastasis of cancer or suppressing aggregation of plaques.

FIELD OF THE INVENTION

This invention relates to novel α-aminoketone derivatives and, inparticular, to novel α-aminoketone derivatives and theirpharmaceutically acceptable salts which strongly inhibit thiol proteasesuch as papain, cathepsin B, cathepsin H, cathepsin L and calpain or thelike.

BACKGROUND OF THE INVENTION

In accordance with the elucidation of the in vivo activity of thiolprotease such as papain, cathepsin B, cathepsin H, cathepsin L, calpainor the like, it has been found that their extraordinary hyperstheniacauses various diseases. Further, in an increased number of thepublications, thiol protease inhibitors are reported as being effectiveon such disease in animal models.

It is considered that thiol protease such as calpain, cathepsin B or thelike takes part in the initial process such as disappearance of Z linethrough the decomposition of muscular fiber protein in the collapse ofskeletal muscle as seen in muscular disease such as muscular Dystrophy,amyotrophy or the like [Taisha (Metabolism), 25, extra-edition"Taisha-byo Highlight (Metabolic Diseases Highlight)", 183 (1988)].Furthermore, E-64-d, namely a thiol protease inhibitor, has beenreported as having life-prolonging effect in experimental musculardystrophy hamster [Journal of Pharmacobio dynamics, 10, 678 (1987)].Accordingly, such thiol protease inhibitors are expected to be useful astherapeutic agents for the treatment of muscular dystrophy, amyotrophyor the like.

The main cause of the post-ischemic cellular disorder which occursduring ischemic diseases such as cardiac infarction, stroke and the likeis active oxygen produced by xanthine oxidase. It has been reportedthat, during the ischemia, the increase in Ca²⁺ concentration results inthe activation of calpain which restrictively degrade xanthinedehydrogenase, a precursor of xanthine oxidase, to give xanthine oxidase[New England Journal of Medicine, 312, p.159, (1985)]. It has also beenreported that the activation of calpain may directly cause the necrosisof myocardial cells or neurocytes [Saishin Igaku, 43, p.783, (1988)].There have been reports that NCO-700, a calpain inhibitor, is effectiveon cardiac infarction when tested on animal models [ArzneimittelForschung/Drug Research, 36, p.190, p.671, (1986)], and that E64-Cinhibits the degradation of microtubule-associated protein after thebrain ischemia [Brain Research, 526, p.177, (1990)]. These reportsindicate that a calpain inhibitor can be useful for the treatment ofischemic diseases such as cardiac infarction, stroke and the like.

The cause of senile plaque which is found specifically in the brain ofpatients suffering from Alzheimer's disease is known to be theprecipitated amyloid, a protein produced by the decomposition of anamyloid precursor protein (APP). Although APP does not give amyloid as anormal metabolite, it may be converted into amyloid under an abnormalmetabolism where protease is extremely activated, and precipitated assenile plaque [Scientific American, (11), p.40, (1991)]. Therefore,protease inhibitor is expected to be useful for the treatment ofAlzheimer's disease.

The activation of calpain has been observed in a brain trauma model ofrabbit [Neurochemical Research, 16, p.483, (1991)]. It has also beenobserved that the administration of leupeptin, a calpain inhibitor, canprotect axon in brain trauma models of rat [Journal of Neurosurgery, 65,p.92, (1986)]. Thus, calpain inhibitors are considered to be useful forimproving the consciousness disturbance or motor disturbance caused bybrain trauma.

It has also been reported that myelin-associated protein exists indendrite of neurocytes is decomposed by calpain [Journal ofNeurochemistry, 47, p.1007, (1986)], indicating that calpain inhibitorsmay be effective on diseases caused by the demyelination of neurocytessuch as multiple sclerosis, peripheral nervous neuropathy and the like.

The main cause of the turbidity during cataract is hydrolytic productsof a water-soluble protein crystalline by protease in lens. There hasbeen observed the increase in calcium concentration in lens ofcataractous animal models and some of human cataract [InvestigativeOphthalmology & Visual Science, 28, p.1702, (1987); Experimental EyeResearch, 34, p.413, (1982)]. The dominant protease contained in lens iscalpain [Lens and Eye Toxicity Research, 6, p.725, (1989)]. These factsindicate that the abnormal sthenia of calpain can be one of the causesof cataract. There is a report that E-64, an inhibitor of calpain, iseffective on cataract in animal models [Investigative Ophthalmology &Visual Science, 32, p.533, (1991)], indicating that calpain inhibitorscan be useful in the treatment of cataract.

Neutrophils, which is deeply associated with inflammation, show thedegranulation or production of superoxides in response to thestimulations by a chemotactic factor or phorbol ester through amechanism appeared to be mediated by protein kinase C (PKC). Calpainparticipates in the activation of PKC in the manner where it promotesthe degranulation and inhibits the production of superoxides [Journal ofBiological Chemistry, 263, p.1915, (1988)]. In another report, theconcentration of cathepsin B in macrophage in rat is 30 to 40 times thatof leukocytes and neutrophils, and the concentration of enzyme ininflammatory macrophage is 6 times that of normal macrophage [Journal ofBiochemistry, 98, p.87, (1985)]. These facts indicate that thiolprotease inhibitors are useful as anti-inflammatory drugs.

The type I allergy reaction is mediated by immunoglobulin E (IgE)produced in the subject immunized with an antigen. Estatin A, a thiolprotease inhibitor, has been reported to specifically inhibit theproduction of IgE without affecting on the production of IgG [TheJournal of Antibiotics, 42, p.1362, (1989)]. Accordingly, thiol proteaseinhibitors are considered to be useful as antiallergic drugs.

In case of necrosis of hepatic cells, it is believed that impairment ofthe cell membrane leads to an increase in the permeability of Ca²⁺, anincrease in intracellular Ca²⁺ concentration, an activation of calpain,and, as the result, the decomposition of its substrate such as skeletalprotein takes place, which results in the death of cells. Accordingly, acalpain inhibitor can be used as a therapeutic agent for fulminanthepatitis.

Cathepsins such as dathepsin B and cathepsin L are involved indecomposition of bone collagen in osteoclast. It has been reported thatadministration of an inhibitor of cathepsins, E-64 or estatin A, to arat which has an enhanced bone destruction by administration ofparathyroid hormone leads to a decrease of calcium concentration andhydroxyproline concentration in blood [Biochemical and BiophysicalResearch Communication, 125, p.441, (1984): Japanese Patent Publication(kokai) No. 218610/1990]. Accordingly, it is believed that an inhibitorof cathepsins can be a therapeutic agent for osteoporosis, hypercalcemiaand the like.

There exist, as a substrate for calpain, sex hormone receptors such asestrogen receptor and androgen receptor, and it is known that calpainactivates these receptors. Accordingly, it is considered that anabnormal sthenia of calpain causes a disease which is suspected to becaused by an abnormal activation of the sex hormone receptors, forexample, breast carcinoma, prostatic carcinoma or prostatomegaly. It isbelieved that an inhibitor for calpain can be a therapeutic agent forthe above disease.

Receptors for epidermal growth factor (EGF) are also considered to beactivated in association with the canceration of cells. It is known thatcalpain activates the EGF receptors as its substrate. Furthermore, ithas been reported that calpain is activated in cells which have beeninfected with adult T cell human leukocyte virus (ATLV/HTLV-1)[Seikagaku, 57, p.1202, (1985)]. On the other hand, it is said thatcathepsin B is greatly involved in a process of cancer metastasisbecause it accelerates decomposition of collagen which is a importantstep for the cancer metastasis or directly decompose collagen, andbecause it has a profound correlation with plasma membrane of neoplasticcells [Tumor Progression and Markers, p.47, (1982); Journal ofBiological Chemistry, 256, p.8536, (1981)]. These facts suggest that athiol protease inhibitor has an ability to suppress the growth of cancercells and prevent the metastasis of cancer.

Activation of platelet causes the aggregation thereof which is a causeof thrombus. It has been reported that an inhibitor of calpain, E-64-d,suppressed aggregation of platelet caused by thrombin [ThrombosisResearch, 57, p.847, (1990)]. Accordingly, the inhibitor of calpain canbe used as an inhibitor against aggregation of platelet.

As described above, an abnormal sthenia of thiol protease causes variousdiseases and the validity of several thiol protease inhibitors in animalmodels has been reported. However, most of the known inhibitors, forexample, epoxy succinate derivatives such as E-64 [Agricultural andBiological Chemistry, 42, p.529, (1978)], E-64-d [Journal ofBiochemistry, 93, p.1305, (1983)], NCO-700 [Japanese Patent Publication(kokai) No. 126879/1983], and estatins A and B [The Journal ofAntibiotics, 42, p.1362, (1989)]or α-substituted ketone of a peptidesuch as chloromethyl ketone [Journal of Biochemistry, 99, p.173, (1986)]and acyloxymethyl ketone [Biochemistry, 30, p.4678, (1991)] areirreversible inhibitors. It is generally said that the irreversibleinhibitors are highly toxic because they are liable to reactnon-specifically with components constituting the living body, otherthan target enzymes. Therefore, there have been few compounds applicableto clinical use so far. Although peptidyl aldehydes such as leupeptin[The Journal of Antibiotics, 22, p.283, (1969)] or calpeptin [Journal ofEnzyme Inhibition, 3, p.195, (1990)] are known as reversible inhibitors,they also have problems in chemical and in vivo stabilities, cellmembrane permeabilities and the like.

SUMMARY OF THE INVENTION

The present inventors investigated into various compounds with the aimof developing reversible inhibitors against thiol protease, which haveexcellent properties in absorbance on oral administration, tissuedistribution and cell membrane permeability, and have found that certainderivatives of ketone have such desired properties.

More particularly, the subject matter of the present invention isdirected to an α-aminoketone derivative having the general formula (I)or a pharmaceutically acceptable salt thereof: ##STR1## wherein, R¹ ishydrogen, ##STR2## (R⁴ is C₁ to C₂₀ alkyl optionally substituted by oneor more substituents selected from the group consisting of C₃ to C₁₅cycloalkyl, C₆ to C₁₄ aryl optionally substituted by one or moresubstituents, a heterocyclic residue optionally substituted by one ormore substituents, C₃ to C₁₅ cycloalkyloxy, C₆ to C₁₄ aryloxy optionallysubstituted by one or more substituents, C₇ to C₂₀ aralkyloxy optionallysubstituted by one or more substituents, and C₆ to C₁₄ arylthiooptionally substituted by one or more substituents; C₂ to C₁₀ alkenyloptionally substituted by C₆ to C₁₄ aryl optionally substituted by oneor more substituents; C₆ to C₁₄ aryl optionally substituted by one ormore substituents; or a heterocyclic residue optionally substituted byone or more substituents), R² and R³ are independently hydrogen or C₁ toC₂₀ alkyl optionally substituted by one or more substituents, ##STR3##is a heterocyclic residue optionally substituted by one or moresubstituents, n is 0 or 1 and m is an integer of from 1 to 5.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is described in detail below. The compoundsaccording to the present invention are α-aminoketone derivatives havingthe general formula (I) or a pharmaceutically acceptable salt thereof:##STR4## wherein, R¹ is hydrogen, ##STR5## (R⁴ is selected from thegroup consisting of C₁ to C₂₀ alkyl (methyl, decyl, icocyl, etc.)optionally substituted by one or more substituents selected from thegroup consisting of C₃ to C₁₅ cycloalkyl (cyclopropyl, cyclononyl,cyclopentadecyl, etc.), C₆ to C₁₄ aryl (phenyl, naphthyl, anthryl, etc.)optionally substituted by one or more substituents (selected from thegroup (hereinafter, referred to as "Group 1") consisting of a halogenatom (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom,etc.), C₁ to C₅ alkyl (methyl, propyl, pentyl, etc.), trifluoromethyl,C₁ to C₅ alkoxy (methoxy, propoxy, pentyloxy, etc.), C₁ to C₅ cyclicacetal residue (methylenedioxy, propylenedioxy, amylenedioxy, etc.),hydroxyl, C₂ to C₆ acyloxy (acetoxy, butyryloxy, valeryloxy, etc.),carboxyl, C₂ to C₆ alkoxycarbonyl (methoxycarbonyl, propoxycarbonyl,pentyloxycarbonyl, etc.), oxo, C₂ to C₆ acyl (acetyl, butyryl, valeryl,etc.), amino, C₁ to C₅ monoalkylamino (methylamino, propylamino,pentylamino, etc.), C₂ to C₁₀ dialkylamino (dimethylamino, methylpropyl,diisopropylamino, etc.), C₂ to C₆ acylamino (acetylamino, valerylamino,etc.), carbamoyl, C₂ to C₆ alkylcarbamoyl (methylcarbamoyl,propylcarbamoyl, pentylcarbamoyl, etc.) and C₆ to C₁₄ aryl (phenyl,naphthyl, anthryl, etc.)), a heterocyclic residue (a heterocyclicresidue (hereinafter, referred to as "Group 2") having a ring of 5 to 10atoms including 1 to 4 hetero atoms selected from the group consistingof oxygen atom, sulfur atom and nitrogen atom, (e.g., furan,dihydrofuran, tetrahydrofuran, pyran, dihydropyran, tetrahydropyran,benzofuran, isobenzofuran, chromene, chroman, isochroman, thiophene,benzothiophene, pyrrole, pyrroline, pyrrolidine, imidazole, imidazoline,imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole, tetrazole,pyridine, pyridineoxide, piperidine, pyrazine, piperazine, pyrimidine,pyridazine, indolizine, indole, indoline, isoindole, isoindoline,indazole, benzimidazole, purine, quinolizine, quinoline, phthalazine,naphtyridine, quinoxaline, quinazoline, cinnoline, pteridine, oxazole,oxazolidine, isooxazole, isoxazolidine, thiazole, thiazolidine,isothiazole, isothiazolidine, dioxane, dithian, morpholine,thiomorpholine) and optionally substituted by one or more substituents(selected from the Group 1), C₃ to C₁₅ cycloalkyloxy (cyclopropyloxy,cyclononyloxy, cyclopentadecyloxy, etc.), C₆ to C₁₄ aryloxy (phenoxy,naphthyloxy, anthryloxy, etc.) optionally substituted by one or moresubstituents (selected from the Group 1), C₇ to C₂₀ aralkyloxy(benzyloxy, phenylpentyloxy, naphthylmethoxy, naphthylethoxy,anthrylmethoxy, etc.) optionally substituted by one or more substituents(selected from the Group 1) and C₆ to C₁₄ arylthio (phenylthio,naphthylthio, anthrylthio, etc.) optionally substituted by one or moresubstituents (selected from the Group 1); C₂ to C₁₀ alkenyl (vinyl,hexeny, decenyl, etc.) optionally substituted by C₆ to C₁₄ aryl (phenyl,naphthyl, anthryl, etc.) optionally substituted by one or moresubstituents (selected from the Group 1); C₆ to C₁₄ aryl (phenyl,naphthyl, anthryl, etc.) optionally substituted by one or moresubstituents (selected from the Group 1)); or a heterocyclic residue(Group 2) optionally substituted by one or more substituents (selectedfrom the Group 1), R² and R³ are independently hydrogen or C₁ to C₂₀alkyl(methyl, decyl, icocyl, etc.) optionally substituted by one or moresubstituent (selected from the Group 1), ##STR6## is a heterocyclicresidue (Group 2) optionally substituted by one or more substituent(selected from the Group 1), n is 0 or 1 and m is an integer of from 1to 5.

Examples of the pharmaceutically acceptable salts are, in the presenceof an acid group, metal salts such as a lithium salt, a sodium salt, apotassium salt, a magnesium salt and a calcium salt or ammonium saltssuch as an ammonium salt, a methyl ammonium salt, a dimethyl ammoniumsalt, a trimethyl ammonium salt and a dicyclohexyl ammonium salt and, inthe presence of a base group, mineral acid salts such as hydrochloride,hydrobromide, sulfate, nitrate and phosphate or organic acid salts suchas methane sulfonate, benzene sulfonate, paratoluene sulfonate, acetate,propionate, tartarate, fumatate, maleate, malate, oxalate, succinate,citrate, benzoate, mandelate, cinnamate and lactate.

The stereochemistry of the double bond of the α-aminoketone derivativeshaving the formula (I) is either one of E, Z and EZ. In addition, thestereochemical configuration of the asymmetric carbon is independentlyspecified by either one of R, S and RS.

Examples of the α-aminoketone derivatives having the formula (I) are setforth in Table 1 and Table 2 below for n=0 and n=1, respectively.

                                      TABLE 1                                     __________________________________________________________________________    (n = O)                                                                        Comp. No.                                                                           R.sup.1            R.sup.3         m                                                                               ##STR7##                          __________________________________________________________________________     1                                                                                   ##STR8##          H               3                                                                                ##STR9##                           2                                                                                   ##STR10##         H               3                                                                                ##STR11##                          3    H                  H               3                                                                                ##STR12##                          4                                                                                   ##STR13##         H               3                                                                                ##STR14##                          5                                                                                   ##STR15##         H               3                                                                                ##STR16##                          6    H                  H               3                                                                                ##STR17##                          7                                                                                   ##STR18##         H               3                                                                                ##STR19##                          8                                                                                   ##STR20##         H               3                                                                                ##STR21##                          9    H                  H               3                                                                                ##STR22##                          10                                                                                  ##STR23##         H               3                                                                                ##STR24##                          11                                                                                  ##STR25##         H               3                                                                                ##STR26##                          12   H                  H               3                                                                                ##STR27##                          13                                                                                  ##STR28##         CH.sub.3        3                                                                                ##STR29##                          14                                                                                  ##STR30##         CH.sub.3        3                                                                                ##STR31##                          15   H                  CH.sub.3        3                                                                                ##STR32##                          16                                                                                  ##STR33##         CH.sub.3        3                                                                                ##STR34##                          17                                                                                  ##STR35##         CH.sub.3        3                                                                                ##STR36##                          18   H                  CH.sub.3        3                                                                                ##STR37##                          19                                                                                  ##STR38##         CH.sub.3        3                                                                                ##STR39##                          20                                                                                  ##STR40##         CH.sub.3        3                                                                                ##STR41##                          21   H                  CH.sub.3        3                                                                                ##STR42##                          22                                                                                  ##STR43##         CH.sub.3        3                                                                                ##STR44##                          23                                                                                  ##STR45##         CH.sub.3        3                                                                                ##STR46##                          24   H                  CH.sub.3        3                                                                                ##STR47##                          25                                                                                  ##STR48##         (CH.sub.3).sub.2 CH                                                                           3                                                                                ##STR49##                          26                                                                                  ##STR50##         (CH.sub.3).sub.2 CH                                                                           3                                                                                ##STR51##                          27   H                  (CH.sub.3).sub.2 CH                                                                           3                                                                                ##STR52##                          28                                                                                  ##STR53##         (CH.sub.3).sub.2 CH                                                                           3                                                                                ##STR54##                          29                                                                                  ##STR55##         (CH.sub.3).sub.2 CH                                                                           3                                                                                ##STR56##                          30   H                  (CH.sub.3).sub.2 CH                                                                           3                                                                                ##STR57##                          31                                                                                  ##STR58##         (CH.sub.3).sub.2 CH                                                                           3                                                                                ##STR59##                          32                                                                                  ##STR60##         (CH.sub.3).sub.2 CH                                                                           3                                                                                ##STR61##                          33   H                  (CH.sub.3).sub.2 CH                                                                           3                                                                                ##STR62##                          34                                                                                  ##STR63##         (CH.sub.3).sub.2 CH                                                                           3                                                                                ##STR64##                          35                                                                                  ##STR65##         (CH.sub.3).sub.2 CH                                                                           3                                                                                ##STR66##                          36   H                  (CH.sub.3).sub.2 CH                                                                           3                                                                                ##STR67##                          37                                                                                  ##STR68##         (CH.sub.3).sub.2 CHCH.sub.2                                                                   3                                                                                ##STR69##                          38                                                                                  ##STR70##         (CH.sub.3).sub.2 CHCH.sub.2                                                                   3                                                                                ##STR71##                          39   H                  (CH.sub.3).sub.2 CHCH.sub.2                                                                   3                                                                                ##STR72##                          40                                                                                  ##STR73##         (CH.sub.3).sub.2 CHCH.sub.2                                                                   3                                                                                ##STR74##                          41                                                                                  ##STR75##         (CH.sub.3).sub.2 CHCH.sub.2                                                                   3                                                                                ##STR76##                          42   H                  (CH.sub.3).sub.2 CHCH.sub.2                                                                   3                                                                                ##STR77##                          43                                                                                  ##STR78##         (CH.sub.3).sub.2 CHCH.sub.2                                                                   3                                                                                ##STR79##                          44                                                                                  ##STR80##         (CH.sub.3).sub.2 CHCH.sub.2                                                                   3                                                                                ##STR81##                          45   H                  (CH.sub.3).sub.2 CHCH.sub.2                                                                   3                                                                                ##STR82##                          46                                                                                  ##STR83##         (CH.sub.3).sub.2 CHCH.sub.2                                                                   3                                                                                ##STR84##                          47                                                                                  ##STR85##         (CH.sub.3).sub.2 CHCH.sub.2                                                                   3                                                                                ##STR86##                          48   H                  (CH.sub.3).sub.2 CHCH.sub.2                                                                   3                                                                                ##STR87##                          49                                                                                  ##STR88##         CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           1                                                                                ##STR89##                          50                                                                                  ##STR90##         CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           1                                                                                ##STR91##                          51   H                  CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           1                                                                                ##STR92##                          52                                                                                  ##STR93##         CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR94##                          53                                                                                  ##STR95##         CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR96##                          54                                                                                  ##STR97##         CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR98##                          55                                                                                  ##STR99##         CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR100##                         56                                                                                  ##STR101##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR102##                         57   H                  CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR103##                         58                                                                                  ##STR104##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR105##                         59                                                                                  ##STR106##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR107##                         60                                                                                  ##STR108##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR109##                         61                                                                                  ##STR110##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR111##                          62                                                                                 ##STR112##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR113##                         63   H                  CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR114##                         64                                                                                  ##STR115##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR116##                         65                                                                                  ##STR117##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR118##                         66   H                  CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR119##                         67                                                                                  ##STR120##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR121##                         68                                                                                  ##STR122##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR123##                         69   H                  CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           3                                                                                ##STR124##                         70                                                                                  ##STR125##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           2                                                                                ##STR126##                         71                                                                                  ##STR127##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           2                                                                                ##STR128##                         72   H                  CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           2                                                                                ##STR129##                         73                                                                                  ##STR130##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           4                                                                                ##STR131##                         74                                                                                  ##STR132##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.                                                            4                                                                                ##STR133##                         75   H                  CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           4                                                                                ##STR134##                         76                                                                                  ##STR135##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           5                                                                                ##STR136##                         77                                                                                  ##STR137##        CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           5                                                                                ##STR138##                         78   H                  CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           5                                                                                ##STR139##                         79                                                                                  ##STR140##                                                                                       ##STR141##     3                                                                                ##STR142##                         80                                                                                  ##STR143##                                                                                       ##STR144##     3                                                                                ##STR145##                          81  H                                                                                                 ##STR146##     3                                                                                ##STR147##                         82                                                                                  ##STR148##                                                                                       ##STR149##     3                                                                                ##STR150##                         83                                                                                  ##STR151##                                                                                       ##STR152##     3                                                                                ##STR153##                         84   H                                                                                                 ##STR154##     3                                                                                ##STR155##                         85                                                                                  ##STR156##                                                                                       ##STR157##     3                                                                                ##STR158##                         86                                                                                  ##STR159##                                                                                       ##STR160##     3                                                                                ##STR161##                         87   H                                                                                                 ##STR162##     3                                                                                ##STR163##                         88                                                                                  ##STR164##                                                                                       ##STR165##     3                                                                                ##STR166##                         89                                                                                  ##STR167##                                                                                       ##STR168##     3                                                                                ##STR169##                         90   H                                                                                                 ##STR170##     3                                                                                ##STR171##                         91                                                                                  ##STR172##        CH.sub.3 SCH.sub.2 CH.sub.2                                                                   3                                                                                ##STR173##                         92                                                                                  ##STR174##        CH.sub.3 SCH.sub.2 CH.sub.2                                                                   3                                                                                ##STR175##                         93   H                  CH.sub.3 SCH.sub.2 CH.sub.2                                                                   3                                                                                ##STR176##                         94                                                                                  ##STR177##        HOCH.sub.2      3                                                                                ##STR178##                         95                                                                                  ##STR179##        HOCH.sub.2      3                                                                                ##STR180##                         96   H                  HOCH.sub.2      3                                                                                ##STR181##                         97                                                                                  ##STR182##        (CH.sub.3).sub.3 COCH.sub.2                                                                   3                                                                                ##STR183##                         98                                                                                  ##STR184##        (CH.sub.3).sub.3 COCH.sub.2                                                                   3                                                                                ##STR185##                         99   H                  (CH.sub.3).sub.3 COCH.sub.2                                                                   3                                                                                ##STR186##                        100                                                                                  ##STR187##                                                                                       ##STR188##     3                                                                                ##STR189##                        101                                                                                  ##STR190##                                                                                       ##STR191##     3                                                                                ##STR192##                        102   H                                                                                                 ##STR193##     3                                                                                ##STR194##                        103                                                                                  ##STR195##                                                                                       ##STR196##     3                                                                                ##STR197##                        104                                                                                  ##STR198##                                                                                       ##STR199##     3                                                                                ##STR200##                        105   H                                                                                                 ##STR201##     3                                                                                ##STR202##                        106                                                                                  ##STR203##                                                                                       ##STR204##     3                                                                                ##STR205##                        107                                                                                  ##STR206##                                                                                       ##STR207##     3                                                                                ##STR208##                        108   H                                                                                                 ##STR209##     3                                                                                ##STR210##                        109                                                                                  ##STR211##        HOOCCH.sub.2 CH.sub.2                                                                         3                                                                                ##STR212##                        110                                                                                  ##STR213##        HOOCCH.sub.2 CH.sub.2                                                                         3                                                                                ##STR214##                        111   H                  HOOCCH.sub.2 CH.sub.2                                                                         3                                                                                ##STR215##                        112                                                                                  ##STR216##                                                                                       ##STR217##     3                                                                                ##STR218##                        113                                                                                  ##STR219##                                                                                       ##STR220##     3                                                                                ##STR221##                        114   H                                                                                                 ##STR222##     3                                                                                ##STR223##                        115                                                                                  ##STR224##                                                                                       ##STR225##     3                                                                                ##STR226##                        116                                                                                  ##STR227##                                                                                       ##STR228##     3                                                                                ##STR229##                        117   H                                                                                                 ##STR230##     3                                                                                ##STR231##                        118                                                                                  ##STR232##        H.sub.2 NCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                  3                                                                                ##STR233##                        119                                                                                  ##STR234##        H.sub.2 NCH.sub.2 CH.sub. 2 CH.sub.2 CH.sub.2                                                 3                                                                                ##STR235##                        120   H                  H.sub.2 NCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                  3                                                                                ##STR236##                        121                                                                                  ##STR237##                                                                                       ##STR238##     3                                                                                ##STR239##                        122                                                                                  ##STR240##                                                                                       ##STR241##     3                                                                                ##STR242##                        123                                                                                  ##STR243##                                                                                       ##STR244##     3                                                                                ##STR245##                        124                                                                                  ##STR246##                                                                                       ##STR247##     3                                                                                ##STR248##                        125                                                                                  ##STR249##                                                                                       ##STR250##     3                                                                                ##STR251##                        126                                                                                  ##STR252##                                                                                       ##STR253##     3                                                                                ##STR254##                        127   H                                                                                                 ##STR255##     3                                                                                ##STR256##                        128                                                                                  ##STR257##                                                                                       ##STR258##     3                                                                                ##STR259##                        129                                                                                  ##STR260##                                                                                       ##STR261##     3                                                                                ##STR262##                        130                                                                                  ##STR263##                                                                                       ##STR264##     3                                                                                ##STR265##                        131                                                                                  ##STR266##                                                                                       ##STR267##     3                                                                                ##STR268##                        132                                                                                  ##STR269##                                                                                       ##STR270##     3                                                                                ##STR271##                        133                                                                                  ##STR272##                                                                                       ##STR273##     3                                                                                ##STR274##                        134                                                                                  ##STR275##                                                                                       ##STR276##     3                                                                                ##STR277##                        135                                                                                  ##STR278##                                                                                       ##STR279##     3                                                                                ##STR280##                        136                                                                                  ##STR281##                                                                                       ##STR282##     3                                                                                ##STR283##                        137                                                                                  ##STR284##                                                                                       ##STR285##     3                                                                                ##STR286##                        138                                                                                  ##STR287##                                                                                       ##STR288##     3                                                                                ##STR289##                        139                                                                                  ##STR290##                                                                                       ##STR291##     3                                                                                ##STR292##                        140                                                                                  ##STR293##                                                                                       ##STR294##     3                                                                                ##STR295##                        141                                                                                  ##STR296##                                                                                       ##STR297##     3                                                                                ##STR298##                        142                                                                                  ##STR299##                                                                                       ##STR300##     3                                                                                ##STR301##                        143                                                                                  ##STR302##                                                                                       ##STR303##     3                                                                                ##STR304##                        144                                                                                  ##STR305##                                                                                       ##STR306##     3                                                                                ##STR307##                        145                                                                                  ##STR308##                                                                                       ##STR309##     3                                                                                ##STR310##                        146                                                                                  ##STR311##                                                                                       ##STR312##     3                                                                                ##STR313##                        147                                                                                  ##STR314##                                                                                       ##STR315##     3                                                                                ##STR316##                        148                                                                                  ##STR317##                                                                                       ##STR318##     3                                                                                ##STR319##                        149   H                                                                                                 ##STR320##     3                                                                                ##STR321##                        150                                                                                  ##STR322##                                                                                       ##STR323##     3                                                                                ##STR324##                        151                                                                                  ##STR325##                                                                                       ##STR326##     3                                                                                ##STR327##                        152   H                                                                                                 ##STR328##     3                                                                                ##STR329##                        153                                                                                  ##STR330##                                                                                       ##STR331##     3                                                                                ##STR332##                        154                                                                                  ##STR333##                                                                                       ##STR334##     3                                                                                ##STR335##                        155   H                                                                                                 ##STR336##     3                                                                                ##STR337##                        156                                                                                  ##STR338##                                                                                       ##STR339##     3                                                                                ##STR340##                        157                                                                                  ##STR341##                                                                                       ##STR342##     3                                                                                ##STR343##                        158                                                                                  ##STR344##                                                                                       ##STR345##     3                                                                                ##STR346##                        159                                                                                  ##STR347##                                                                                       ##STR348##     3                                                                                ##STR349##                        160   H                                                                                                 ##STR350##     3                                                                                ##STR351##                        161                                                                                  ##STR352##                                                                                       ##STR353##     3                                                                                ##STR354##                        162                                                                                  ##STR355##                                                                                       ##STR356##     3                                                                                ##STR357##                        163   H                                                                                                 ##STR358##     3                                                                                ##STR359##                        164                                                                                  ##STR360##                                                                                       ##STR361##     3                                                                                ##STR362##                        165                                                                                  ##STR363##                                                                                       ##STR364##     3                                                                                ##STR365##                        166   H                                                                                                 ##STR366##     3                                                                                ##STR367##                        167                                                                                  ##STR368##                                                                                       ##STR369##     3                                                                                ##STR370##                        168                                                                                  ##STR371##                                                                                       ##STR372##     3                                                                                ##STR373##                        169   H                                                                                                 ##STR374##     3                                                                                ##STR375##                        170                                                                                  ##STR376##                                                                                       ##STR377##     3                                                                                ##STR378##                        171                                                                                  ##STR379##                                                                                       ##STR380##     3                                                                                ##STR381##                        172   H                                                                                                 ##STR382##     3                                                                                ##STR383##                        173                                                                                  ##STR384##                                                                                       ##STR385##     3                                                                                ##STR386##                        174                                                                                  ##STR387##                                                                                       ##STR388##     3                                                                                ##STR389##                        175   H                                                                                                 ##STR390##     3                                                                                ##STR391##                        176                                                                                  ##STR392##                                                                                       ##STR393##     3                                                                                ##STR394##                        177                                                                                  ##STR395##                                                                                       ##STR396##     3                                                                                ##STR397##                        178   H                                                                                                 ##STR398##     3                                                                                ##STR399##                        179                                                                                  ##STR400##                                                                                       ##STR401##     3                                                                                ##STR402##                        180                                                                                  ##STR403##                                                                                       ##STR404##     3                                                                                ##STR405##                        181   H                                                                                                 ##STR406##     3                                                                                ##STR407##                        182                                                                                  ##STR408##                                                                                       ##STR409##     3                                                                                ##STR410##                        183                                                                                  ##STR411##                                                                                       ##STR412##     3                                                                                ##STR413##                        184   H                                                                                                 ##STR414##     3                                                                                ##STR415##                        185                                                                                  ##STR416##                                                                                       ##STR417##     3                                                                                ##STR418##                        186                                                                                  ##STR419##                                                                                       ##STR420##     3                                                                                ##STR421##                        187                                                                                  ##STR422##                                                                                       ##STR423##     3                                                                                ##STR424##                        188   H                                                                                                 ##STR425##     3                                                                                ##STR426##                        189                                                                                  ##STR427##                                                                                       ##STR428##     3                                                                                ##STR429##                        190                                                                                  ##STR430##                                                                                       ##STR431##     3                                                                                ##STR432##                        191                                                                                  ##STR433##                                                                                       ##STR434##     3                                                                                ##STR435##                        192                                                                                  ##STR436##                                                                                       ##STR437##     3                                                                                ##STR438##                        193                                                                                  ##STR439##                                                                                       ##STR440##     3                                                                                ##STR441##                        194                                                                                  ##STR442##                                                                                       ##STR443##     3                                                                                ##STR444##                        195                                                                                  ##STR445##                                                                                       ##STR446##     3                                                                                ##STR447##                        196   H                                                                                                 ##STR448##     3                                                                                ##STR449##                        197                                                                                  ##STR450##                                                                                       ##STR451##     3                                                                                ##STR452##                        198                                                                                  ##STR453##                                                                                       ##STR454##     3                                                                                ##STR455##                        199   H                                                                                                 ##STR456##     3                                                                                ##STR457##                        200                                                                                  ##STR458##                                                                                       ##STR459##     3                                                                                ##STR460##                        201                                                                                  ##STR461##                                                                                       ##STR462##     3                                                                                ##STR463##                        202   H                                                                                                 ##STR464##     3                                                                                ##STR465##                        203                                                                                  ##STR466##                                                                                       ##STR467##     3                                                                                ##STR468##                        204                                                                                  ##STR469##                                                                                       ##STR470##     3                                                                                ##STR471##                        205   H                                                                                                 ##STR472##     3                                                                                ##STR473##                        206                                                                                  ##STR474##                                                                                       ##STR475##     3                                                                                ##STR476##                        207                                                                                  ##STR477##                                                                                       ##STR478##     3                                                                                ##STR479##                        208   H                                                                                                 ##STR480##     3                                                                                ##STR481##                        __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    (n = 1)                                                                        No.Comp.                                                                          R.sup.1          R.sup.2          R.sup.3       m                                                                               ##STR482##             __________________________________________________________________________    209                                                                                ##STR483##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    H             3                                                                                ##STR484##             210                                                                                ##STR485##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    H             3                                                                                ##STR486##             211                                                                                ##STR487##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    H             3                                                                                ##STR488##             212                                                                                ##STR489##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    H             3                                                                                ##STR490##             213                                                                                ##STR491##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3      3                                                                                ##STR492##             214                                                                                ##STR493##                                                                                     ##STR494##      CH.sub.3      3                                                                                ##STR495##             215                                                                                ##STR496##                                                                                     ##STR497##      CH.sub.3      3                                                                                ##STR498##             216                                                                                ##STR499##                                                                                     ##STR500##      CH.sub.3      3                                                                                ##STR501##             217 H                                                                                               ##STR502##      CH.sub.3      3                                                                                ##STR503##             218                                                                                ##STR504##                                                                                     ##STR505##      CH.sub.3      3                                                                                ##STR506##             219                                                                                ##STR507##                                                                                     ##STR508##      CH.sub.3      3                                                                                ##STR509##             220                                                                                ##STR510##                                                                                     ##STR511##      CH.sub.3      3                                                                                ##STR512##             221                                                                                ##STR513##                                                                                     ##STR514##      CH.sub.3      3                                                                                ##STR515##             222                                                                                ##STR516##                                                                                     ##STR517##      CH.sub.3      3                                                                                ##STR518##             223                                                                                ##STR519##                                                                                     ##STR520##      CH.sub.3      3                                                                                ##STR521##             224                                                                                ##STR522##                                                                                     ##STR523##      CH.sub.3      3                                                                                ##STR524##             225                                                                                ##STR525##                                                                                     ##STR526##      CH.sub.3      3                                                                                ##STR527##             226                                                                                ##STR528##                                                                                     ##STR529##      CH.sub.3      3                                                                                ##STR530##             227                                                                                ##STR531##                                                                                     ##STR532##      CH.sub.3      3                                                                                ##STR533##             228                                                                                ##STR534##                                                                                     ##STR535##      CH.sub.3      3                                                                                ##STR536##             229                                                                                ##STR537##                                                                                     ##STR538##      CH.sub.3      3                                                                                ##STR539##             230 H                                                                                               ##STR540##      CH.sub.3      3                                                                                ##STR541##             231                                                                                ##STR542##                                                                                     ##STR543##      CH.sub.3      3                                                                                ##STR544##             232                                                                                ##STR545##                                                                                     ##STR546##      CH.sub.3      3                                                                                ##STR547##             233                                                                                ##STR548##                                                                                     ##STR549##      CH.sub.3      3                                                                                ##STR550##             234                                                                                ##STR551##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    (CH.sub.3).sub.2 CH                                                                         3                                                                                ##STR552##             235                                                                                ##STR553##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    (CH.sub.3).sub.2 CH                                                                         3                                                                                ##STR554##             236                                                                                ##STR555##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    (CH.sub.3).sub.2 CH                                                                         3                                                                                ##STR556##             237                                                                                ##STR557##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    (CH.sub.3).sub.2 CH                                                                         3                                                                                ##STR558##             238                                                                                ##STR559##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    (CH.sub.3).sub.2 CHCH.sub.2                                                                 3                                                                                ##STR560##             239                                                                                ##STR561##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    (CH.sub.3).sub.2 CHCH.sub.2                                                                 3                                                                                ##STR562##             240                                                                                ##STR563##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         1                                                                                ##STR564##             241                                                                                ##STR565##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         1                                                                                ##STR566##             242                                                                                ##STR567##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         1                                                                                ##STR568##             243                                                                                ##STR569##      (CH.sub.3).sub.2 CHCH.sub. 2                                                                   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         1                                                                                ##STR570##             244                                                                                ##STR571##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         2                                                                                ##STR572##             245                                                                                ##STR573##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         2                                                                                ##STR574##             246                                                                                ##STR575##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         2                                                                                ##STR576##             247                                                                                ##STR577##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         2                                                                                ##STR578##             248                                                                                ##STR579##      H                CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR580##             249                                                                                ##STR581##      CH.sub.3         CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR582##             250                                                                                ##STR583##      (CH.sub.3).sub.2 CH                                                                            CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR584##             251                                                                                ##STR585##      (CH.sub.3).sub.2 CH                                                                            CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR586##             252 H                (CH.sub.3).sub.2 CH                                                                            CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR587##             253                                                                                ##STR588##      (CH.sub.3).sub.2 CH                                                                            CH.sub.3 CH.sub. 2 CH.sub.2                                                                 3H.sub.2                                                                         ##STR589##             254                                                                                ##STR590##      (CH.sub.3).sub.2 CH                                                                            CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR591##             255                                                                                ##STR592##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR593##             256                                                                                ##STR594##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR595##             257                                                                                ##STR596##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR597##             258                                                                                ##STR598##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR599##             259                                                                                ##STR600##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR601##             260                                                                                ##STR602##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR603##             261 H                (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR604##             262                                                                                ##STR605##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR606##             263                                                                                ##STR607##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR608##             264                                                                                ##STR609##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR610##             265                                                                                ##STR611##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR612##             266                                                                                ##STR613##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR614##             267                                                                                ##STR615##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR616##             268                                                                                ##STR617##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR618##             269                                                                                ##STR619##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR620##             270                                                                                ##STR621##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR622##             271                                                                                ##STR623##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR624##             272                                                                                ##STR625##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR626##             273                                                                                ##STR627##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR628##             274                                                                                ##STR629##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR630##             275                                                                                ##STR631##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR632##             276                                                                                ##STR633##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR634##             277                                                                                ##STR635##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR636##             278                                                                                ##STR637##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR638##             279                                                                                ##STR639##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR640##             280                                                                                ##STR641##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR642##             281                                                                                ##STR643##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR644##             282                                                                                ##STR645##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR646##             283                                                                                ##STR647##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR648##             284                                                                                ##STR649##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR650##             285                                                                                ##STR651##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR652##             286                                                                                ##STR653##      CH.sub.3 CH.sub. 2 CH.sub.2 CH.sub.2                                                           CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR654##             287                                                                                ##STR655##                                                                                     ##STR656##      CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR657##             288                                                                                ##STR658##      CH.sub.3 SCH.sub.2 CH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR659##             289                                                                                ##STR660##                                                                                     ##STR661##      CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR662##             290                                                                                ##STR663##                                                                                     ##STR664##      CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR665##             291                                                                                ##STR666##      H.sub.2 NCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                   CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR667##             292                                                                                ##STR668##                                                                                     ##STR669##      CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR670##             293                                                                                ##STR671##                                                                                     ##STR672##      CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR673##             294                                                                                ##STR674##                                                                                     ##STR675##      CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR676##             295                                                                                ##STR677##                                                                                     ##STR678##      CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR679##             296                                                                                ##STR680##                                                                                     ##STR681##      CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR682##             297                                                                                ##STR683##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR684##             298                                                                                ##STR685##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR686##             299                                                                                ##STR687##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                           2             3                                                                                ##STR688##             300                                                                                ##STR689##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR690##             301 H                (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR691##             302                                                                                ##STR692##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR693##             303                                                                                ##STR694##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR695##             304                                                                                ##STR696##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR697##             305                                                                                ##STR698##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         4                                                                                ##STR699##             306                                                                                ##STR700##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         4                                                                                ##STR701##             307                                                                                ##STR702##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         4                                                                                ##STR703##             308                                                                                ##STR704##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         4                                                                                ##STR705##             309                                                                                ##STR706##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         5                                                                                ##STR707##             310                                                                                ##STR708##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         5                                                                                ##STR709##             311                                                                                ##STR710##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         5                                                                                ##STR711##             312                                                                                ##STR712##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         5                                                                                ##STR713##             313                                                                                ##STR714##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR715##   3                                                                                ##STR716##             314                                                                                ##STR717##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR718##   3                                                                                ##STR719##             315                                                                                ##STR720##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR721##   3                                                                                ##STR722##             316                                                                                ##STR723##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR724##   3                                                                                ##STR725##             317                                                                                ##STR726##      CH.sub.3                                                                                        ##STR727##   3                                                                                ##STR728##             318                                                                                ##STR729##      (CH.sub.3).sub.2 CH                                                                             ##STR730##   3                                                                                ##STR731##             319                                                                                ##STR732##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR733##   3                                                                                ##STR734##             320                                                                                ##STR735##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR736##   3                                                                                ##STR737##             321                                                                                ##STR738##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR739##   3                                                                                ##STR740##             322                                                                                ##STR741##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR742##   3                                                                                ##STR743##             323                                                                                ##STR744##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR745##   3                                                                                ##STR746##             324                                                                                ##STR747##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR748##   3                                                                                ##STR749##             325 H                (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR750##   3                                                                                ##STR751##             326                                                                                ##STR752##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR753##   3                                                                                ##STR754##             327                                                                                ##STR755##      (CH.sub.3).sub.2 CHCH.sub. 2                                                                    ##STR756##   3                                                                                ##STR757##             328                                                                                ##STR758##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR759##   3                                                                                ##STR760##             329                                                                                ##STR761##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR762##   3                                                                                ##STR763##             330                                                                                ##STR764##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR765##   3                                                                                ##STR766##             331                                                                                ##STR767##                                                                                     ##STR768##                                                                                     ##STR769##   3                                                                                ##STR770##             332                                                                                ##STR771##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR772##   3                                                                                ##STR773##             333                                                                                ##STR774##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR775##   3                                                                                ##STR776##             334                                                                                ##STR777##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR778##   3                                                                                ##STR779##             335                                                                                ##STR780##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR781##   3                                                                                ##STR782##             336                                                                                ##STR783##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR784##   3                                                                                ##STR785##             337                                                                                ##STR786##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR787##   3                                                                                ##STR788##             338                                                                                ##STR789##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR790##   3                                                                                ##STR791##             339 H                (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR792##   3                                                                                ##STR793##             340                                                                                ##STR794##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR795##   3                                                                                ##STR796##             341                                                                                ##STR797##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR798##   3                                                                                ##STR799##             342                                                                                ##STR800##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR801##   3                                                                                ##STR802##             343                                                                                ##STR803##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR804##   3                                                                                ##STR805##             344                                                                                ##STR806##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR807##   3                                                                                ##STR808##             345                                                                                ##STR809##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR810##   3                                                                                ##STR811##             346                                                                                ##STR812##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR813##   3                                                                                ##STR814##             347                                                                                ##STR815##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR816##   3                                                                                ##STR817##             348                                                                                ##STR818##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR819##   3                                                                                ##STR820##             349                                                                                ##STR821##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR822##   3                                                                                ##STR823##             350                                                                                ##STR824##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR825##   3                                                                                ##STR826##             351                                                                                ##STR827##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR828##   3                                                                                ##STR829##             352                                                                                ##STR830##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR831##   3                                                                                ##STR832##             353                                                                                ##STR833##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR834##   3                                                                                ##STR835##             354                                                                                ##STR836##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR837##   3                                                                                ##STR838##             355                                                                                ##STR839##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR840##   3                                                                                ##STR841##             356                                                                                ##STR842##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR843##   3                                                                                ##STR844##             357                                                                                ##STR845##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR846##   3                                                                                ##STR847##             358                                                                                ##STR848##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR849##   3                                                                                ##STR850##             359                                                                                ##STR851##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR852##   3                                                                                ##STR853##             360                                                                                ##STR854##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR855##   3                                                                                ##STR856##             361                                                                                ##STR857##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR858##   3                                                                                ##STR859##             362                                                                                ##STR860##      (CH.sub. 3).sub.2 CHCH.sub.2                                                                    ##STR861##   3                                                                                ##STR862##             363                                                                                ##STR863##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR864##   3                                                                                ##STR865##             364                                                                                ##STR866##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR867##   3                                                                                ##STR868##             365                                                                                ##STR869##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR870##   3                                                                                ##STR871##             366                                                                                ##STR872##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR873##   3                                                                                ##STR874##             367 H                (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR875##   3                                                                                ##STR876##             368                                                                                ##STR877##      CH.sub.3).sub.2 CHCH.sub.2                                                                      ##STR878##   3                                                                                ##STR879##             369                                                                                ##STR880##      CH.sub.3).sub.2 CHCH.sub.2                                                                      ##STR881##   3                                                                                ##STR882##             370                                                                                ##STR883##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR884##   3                                                                                ##STR885##             371                                                                                ##STR886##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR887##   3                                                                                ##STR888##             372                                                                                ##STR889##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR890##   3                                                                                ##STR891##             373                                                                                ##STR892##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR893##   3                                                                                ##STR894##             374                                                                                ##STR895##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR896##   3                                                                                ##STR897##             375                                                                                ##STR898##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR899##   3                                                                                ##STR900##             376                                                                                ##STR901##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR902##   3                                                                                ##STR903##             377                                                                                ##STR904##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR905##   3                                                                                ##STR906##             378                                                                                ##STR907##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR908##   3                                                                                ##STR909##             379 H                (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR910##   3                                                                                ##STR911##             380                                                                                ##STR912##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR913##   3                                                                                ##STR914##             381                                                                                ##STR915##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR916##   3                                                                                ##STR917##             382                                                                                ##STR918##      (CH.sub.3).sub.2 CHCH.sub.2                                                                     ##STR919##   3                                                                                ##STR920##             383                                                                                ##STR921##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR922##             384 H                (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR923##             385                                                                                ##STR924##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR925##             386                                                                                ##STR926##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR927##             387                                                                                ##STR928##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR929##             388                                                                                ##STR930##      (CH.sub.3).sub.2 CHCH.sub.2                                                                    CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                         3                                                                                ##STR931##             __________________________________________________________________________

A method of preparing the compound according to the present invention isnow described. Alpha-aminoketone derivatives having the aforementionedgeneral formula (I) my be prepared through, but not limited to, thefollowing method. ##STR932##

In the above mentioned general formula (I), R¹, R², R³, R⁴, ##STR933## Xand m are as hereinabove defined while Boc is a tert-butoxycarbonylgroup.

A hydroxamic acid derivative having the formula (II), prepared through aknown method as disclosed in Synthesis, p.676, (1983), is dissolved in asolvent such as diethylether, tetrahydrofuran or dimethoxyethane, whichis subjected to the Grignard reaction at -78° to 0° C. with a Grignardreagent having the formula (III). The reactant is then post-treated withan acid such as a dilute hydrochloric acid, which produces a compoundhaving the formula (IV). Subsequently, the Boc group of the compound(IV) is treated in any one of common methods to provide the aminoketonederivative having the formula (V) or their salts. Such methods includetreatment of the Boc group using, for example, hydrochloricacid-ethanol, hydrogen chloride containing ethyl acetate, hydrogenchloride containing dioxane, hydrogen chloride containing ethanol orhydrogen bromide containing acetic acid. The compound (V) is dissolvedin a solvent such as diethylether, tetrahydrofuran, dioxane, ethylacetate, dichloromethane, chloroform, 1,2-dichloroethane,dimethylformamide or N-methylpyrrolidone, which is then reacted with thechloroformate derivative having the formula (VI) in the presence of abase such as triethylamine or pyridine. This results in production ofthe compound having the formula (VII). Reaction of the compound (V) withacid chloride having the formula (VIII) provides the compound having theformula (IX). On the other hand, the compound having the formula (XI) isproduced when the compound (V) and the carboxyl group of the amino acidderivative having the formula (X) are activated with a condensing agentsuch as isobutyl chloroformate, diphenylphosphoryl azide,carbonyldiimidazole or dicyclohexylcarbodiimide in the presence of abase such as triethylamine or pyridine, if necessary, and reacted witheach other in the presence of a base such as triethylamine or pyridine.

For applying the compound according to the present invention to theclinical fields, the ratio of the therapeutically active componentrelative to the carrier can be altered within the range between 1% to99% by weight. For example, the compound according to the presentinvention may be formed into various dosage forms for oraladministration. Such dosage forms include granules, fine granules,powders, tablets, hard gelatin capsules, soft elastic capsules, syrup,emulsion, suspension and liquid preparation. Alternatively, the compoundmay be used as parenteral injections for intravenous, intramuscular orsubcutaneous injections. It may also be used as a suppository. Inaddition, the compound may be formed into powders for injection andprepared whenever it becomes necessary. The drug according to thepresent invention can be prepared with adequate organic or inorganicmedical diluent and/or solid or liquid carrier suitable for oral, rectalor parenteral administration. The vehicles, fillers, diluents andexcipient preferably used for solid preparation are: lactose, sucrose,starch, talc, cellulose, dextrin, kaolin and calcium carbonate. Theliquid preparation for oral administration, i.e., emulsion, syrup andsuspension include commonly used inactive diluent such as water andvegetable oil. The preparation may contain, other than the inactivediluent, auxiliaries such as moistening agents, suspending agents,sweetening agents, aromatic agents, coloring agents and preservatives.Alternatively, the preparation may be contained in, as the liquidpreparation, a capsule made of an absorbed material such as gelatin.Examples of the solvents and suspending agents preferably used forpreparing the preparation for the parenteral administration, i.e.,injection and suppository are: water, propylene glycol, polyethyleneglycol, benzyl alcohol, ethyl oleate and lecithin. Exemplified bases forthe suppository include cacao butter, emulsificated cacao butter, laurintallow and witepsol. The preparation can be made according to any one ofordinary methods.

The dosage relating to the present compound for oral administration toadults is generally in the range of between 0.01 to 1,000 mg as thedaily dose. It is, however, preferable to control the dosage dependingon the age, the degree of diseases and the symptom. The daily dose ofthe drug according to the present invention may be administered once aday. The same dose may also be administered two or three times a day atsuitable intervals or on alternate days or so.

The daily dose of 0.001 to 100 mg relating to the present compound forinjection to adults is preferably administered continuously orintermittently.

The foregoing features of the present invention will be more readilyapparent in the context of a specifically delineated set of examples anda reference. However, it should be understood that the present inventionis not limited to those particular examples and the reference as long asnot being depart from the spirit and scope of the appended claims.

REFERENCE 1 Preparation of 1-chloro-4-(2-furyl)butane

Furan (1.36 g) was dissolved in tetrahydrofuran (50 ml) and cooled to-25° C. Hexane solution (12.5 ml) of n-butyllithium of 1.68 mol/l wasadded to the reaction solution, which was stirred at -15° C. for 4hours. Subsequently, 1-bromo-4-chlorobutane (3.43 g) was dissolved intetrahydrofuran (2.5 ml) and added to the reaction solution. Thissolution was further stirred at -15° C. for 1 hour and stood overnightat room temperature. The reaction solution was poured into icy water andextracted with ether. The extracted solution was successively washedwith water, a saturated ammonium chloride solution and a saturatedsodium chloride solution. It was then dried over magnesium sulfate andfiltered. The filtrate was concentrated and the resultant oil-likeproduct was purified by distillation under reduced pressure (130° C./12mmHg). The object compound (2.87 g) was obtained in the form of oil.

Yield: 91% NMR (CDCl₃, δ): 1.80(m, 4H), 2.66(t, J=6.5 Hz, 2H), 3.55(t,J=6.3 Hz, 2H), 6.00(dd, J=2.4 Hz, 0.8 Hz, 1H), 6.28(m, 1H), 7.30(dd,J=1.8 Hz, 0.6 Hz, 1H).

EXAMPLE 1 Preparation of(S)-6-tert-butoxycarbonylamino-1-(2-furyl)-5-decanone (Compound No. 73in Table 1)

Metal magnesium turnings (869 mg) were added to ether (5 ml), to which1-chloro-4-(2-furyl)butane (2.87 g) obtained in the Reference 1 in ether(3 ml) was added dropwise. A drop of 1,2-dibromoethane was added to thereaction solution, which was refluxed gently for 2 hours. The reactionsolution was then cooled to -20° C., to whichN-tert-butoxycarbonyl-N'-methoxy-N'-methyl L-norleucineamido (1.24g)dissolved in ether (3 ml) was added dropwise. The reaction solution wasstirred at -15° C. for 1 hour and further stirred at 0° C. for 1.5hours. This solution was poured into a cooled solution of 1Nhydrochloric acid and extracted with ether. The extracted solution wassuccessively washed with water, a saturated sodium hydrogencarbonatesolution and a saturated sodium chloride solution. It was dried overmagnesium sulfate and filtered. The filtrate was concentrated andpurified by the silica gel column chromatography (eluent hexane:ethylacetate 6:1). The object compound (1.33 g) was obtained in the form ofoil.

Yield: 87% IR: (KBr, cm⁻¹): 3356, 1707, 1508 NMR (CDCl₃, δ): 0.89(m,3H), 1.13-1.40(m, 1H), 1.44(s, 9H), 1.52(m, 1H), 1.57-1.68(m, 4H),1.80(m, 1H), 2.50(m, 2H), 2.63(m, 2H), 4.29(m, 1H), 5.16(d, J=7.1 Hz,1H), 5.98(dd, J=3.2 Hz, 0.8 Hz, 1H), 6.27(dd, J=3.1 Hz, 1.9 Hz, 1H),7.29(dd, J=1.8 Hz, 0.8 Hz, 1H)

EXAMPLE 2 Preparation of (S)-6-amino-1-(2-furyl)-5-decanonehydrochloride (Compound No. 75 in Table 1)

(S)-6-tert-Butoxycarbonylamino-1-(2-furyl)-5-decanone (214 mg) obtainedin Example 1 was dissolved in 2 ml solution of ethyl acetate containing4N hydrogen chloride and stirred for 20 minutes. Then, n-hexane (10 ml)was added to the reaction solution, which was concentrated to dryness toobtain the object compound.

NMR (CDCl₃, δ): 0.96(t, J=6.8 Hz, 3H), 1.10-1.30(m, 4H), 1.30-1.75(m,4H), 1.80(m, 1H), 1.99(m, 1H), 2.50-2.75(m, 4H), 4.12(dd, J=7.4 Hz, 4.2Hz, 1H), 6.02(dd, J=3.2 Hz, 0.7 Hz, 1H), 6.27(dd, J=3.0 Hz, 2.0 Hz, 1H),7.32(t, J=1.1Hz,

EXAMPLE 3 Preparation of(S)-6-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino)-1-(2-furyl)-5-decanone(Compound No. 305 in Table 2)

N-Benzyloxycarbonyl-L-leucine (185 mg) was dissolved in methylenechloride (5 ml) and cooled to -5° C., to which triethylamine (70 mg) andisobutyl chloroformate (87 mg) were added. The resultant solution wasstirred for 15 minutes. Added thereto were triethylamine (64 mg) and asolution of (S)-6-amino1-(2-furyl)-5-decanone hydrochloride obtained inExample 2 dissolved in methylene chloride (3 ml). One hour later, 0.5Nhydrochloric acid solution (10 ml) was added thereto, which was thenextracted with methylene chloride. The extracted solution wassuccessively washed with water, a saturated sodium hydrogencarbonatesolution and a saturated sodium chloride solution. It was dried overmagnesium sulfate and filtered. The filtrate was concentrated andpurified by the silica gel column chromatography (eluent hexane:ethylacetate 4:1). The resultant product was re-crystallized from a mixedsolution of hexane and ethyl acetate to obtain the object compound (199mg).

Yield: 65% Melting Point: 92°-93° C. IR: (KBr, cm⁻¹): 3306, 1690, 1625,1535 NMR (CDCl₃, δ): 0.87(t, J=6.6 Hz, 3H), 0.94(d, J=5.8 Hz, 6H),1.06-1.20(m, 4H), 1.20-1.73(m, 8H), 1.85(m, 1H), 2.50(m, 2H), 2.63(m,2H), 4.19(m, 1H), 4.56(ddd, J=7.2 Hz, 7.2 Hz, 4.6 Hz, 1H), 5.11 (s, 2H),5.14(s, 1H), 5.98(d, J=3.1 Hz, 1H), 6.27(s, 1H), 6.57(d, J=6.4 Hz, 1H),7.29 (d, J=0.9 Hz, 1H), 7.35(s, 5H)

Similar operations were repeated to those made in Reference 1 andExamples 1 through 3 to prepare the following compounds. Values ofphysical properties thereof are shown below.

EXAMPLE 4 Preparation of (S)-5-tert-butoxycarbonylamino-1-(2-furyl)-4-nonanone (Compound No. 53 in Table 1)

NMR (CDCl₃, δ): 0.89(t, J=7.1 Hz, 3H), 1.12-1.58(m, 5H), 1.44(s, 9H),1.81(m, 1H), 1.95(m, 2H), 2.53(m, 2H), 2.65(t, J=7.3 Hz, 2H), 4.26(m,1H), 5.17(d, J=7.3 Hz, 1H), 5.99(d, J=3.1 Hz, 1H), 6.27(m, 1H), 7.29(m,1H)

EXAMPLE 5 Preparation of(S)-5-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino)-1-(2-furyl)-4-nonanone(Compound No. 257 in Table 2)

Melting Point: 62°-64° C. IR: (KBr, cm⁻¹): 3283, 1721, 1686, 1655, 1535NMR (CDCl₃, δ): 0.86(t, J=6.8 Hz, 3H), 0.94(d, J=6.1 Hz, 6H),1.07-1.40(m, 4H), 1.40-1.72(m, 1H), 1.85(m, 1H), 1.94(t, J=7.1 Hz, 2H),2.44-2.58(m, 2H), 2.65(t, J=7.1 Hz, 2H), 5.99(dd, J=3.1 Hz, 0.6 Hz, 1H),6.27(dd, J=3.2 Hz, 2.0 Hz, 1H), 6.58(d, J=7.2 Hz, 1H), 7.30(dd, J=1.8Hz, 0.7 Hz, 1H), 7.35(s, 5H)

EXAMPLE 6 Preparation of(S)-5-benzyloxycarbonylamino-1-(2-furyl)-4-nonanone (Compound No. 55 inTable 1)

NMR (CDCl₃, δ): 0.87(t, J=6.7 Hz, 3H), 1.07-1.40(m, 4H), 1.43-1.61(m,1H), 1.66-2.01(m, 3H), 2.38-2.58(m, 2H), 2.64(t, J=7.2 Hz, 2H), 4.36(m,1H), 5.09(s, 2H), 5.46(d, J=7.5 Hz, 1H), 5.98(d, J=2.8 Hz, 1H), 6.26(m,1H), 7.23-7.41(m, 6H)

EXAMPLE 7 Preparation of(S)-5-tert-butoxycarbonylamino-1-(2-thienyl)-4-nonanone (Compound No. 64in Table 1)

Melting Point: 50.5°-52.5° C. IR: (KBr, cm⁻¹): 3380, 1721, 1688 NMR(CDCl₃, δ): 0.88(t, J=7.1 Hz, 3H), 1.18-1.37(m, 4H), 1.43(s, 9H),1.49(m, 1H), 1.76(m, 1H), 1.78(tt, J=7.3 Hz, 7.3 Hz, 2H), 2.53(t, J=7.0Hz, 1H), 2.54(t, J=7.4 Hz, 1H), 2.85(t, J=7.3 Hz, 2H), 4.27(m, 1H),5.14(d, J=6.5 Hz, 1H), 6.78(d, J=2.5 Hz, 1H), 6.92(dd, J=5.0 Hz, 3.4 Hz,1H), 7.12(dd, J=5.1 Hz, 1.0 Hz, 1H)

EXAMPLE 8 Preparation of (S) -5-amino-1-(2-thienyl)-4-nonanonehydrochloride (Compound No. 66 in Table 1 )

Melting Point: 75°-78° C. IR: (KBr, cm⁻¹): 2932, 1723 NMR (CD3OD, δ):0.94(t, J=6.8 Hz, 3H), 1.20-1.50(m, 4H), 1.79(m, 1H), 1.90(m, 1H),1.98(tt, J=7.2 Hz, 7.2 Hz, 2H), 2.64(t, J=7.3 Hz, 1H), 2.67(t, J=7.4 Hz,1H), 2.88(t, J=7.3 Hz, 2H), 4.12(dd, J=7.5 Hz, 4.3 Hz, 1H), 6.82(dd, J=3.4 Hz, 0.9 Hz, 1H), 6.91(dd, J=5.0 Hz, 3.4 Hz, 1H), 7.19(dd, J=5.0 Hz,1.1 Hz, 1H)

EXAMPLE 9 Preparation of(S)-5-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino)-1-(2-thienyl)-4-nonanone(Compound No. 298 in Table 2)

Melting Point: 65°-67° C. IR: (KBr, cm⁻¹): 3281, 1723, 1688, 1655 NMR(CDCl₃, δ): 0.86(t, J=6.7 Hz, 3H), 0.94(d, J=6.1 Hz, 6H), 1.10-1.40(m,4H), 1.40-1.75(m, 3H), 1.79(m, 1H), 1.84(m, 1H), 1.98(tt, J=7.2 Hz, 7.2Hz, 2H), 2.54(m, 2H), 2.85(t, J=7.3 Hz, 2H), 4.20(m, 1H), 4.54(m, 1H),5.11(s, 2H) , 5.17(d, J=7.6 Hz, 1H), 6.57(d, J=6.9 Hz, 1H), 6.78(d,J=2.6 Hz, 1H), 6.92(dd, J=5.1Hz, 3.4 Hz, 1H), 7.12(dd, J=5.1 Hz, 1.1 Hz,1H), 7.34(s, 5H)

EXAMPLE 10 Preparation of(S)-5-((S)-2-tert-butoxycarbonylamino-4-methylvalerylamino)-1-(2-thienyl)4-nonanone (Compound No. 383 in Table 2)

Melting Point: 70°-72° C. IR: (KBr, cm⁻¹): 3335, 1721, 1682, 1657 NMR(CDCl₃, δ): 0.87(t, J=6.7 Hz, 3H), 0.93(d, J=6.0 Hz, 3H), 0.94(d, J=6.2Hz, 3H), 1.15-1.40(m, 4H), 1.44(s, 9H), 1.49(m, 1H), 1.58-1.69(m, 3H),1.84(m, 1H), 1.98(tt, J=7.3 Hz, 7.3 Hz, 2H), 2.53(t, J=6.9 Hz, 1H),2.55(t, J=7.5 Hz, 1H), 2.85(t, J=7.2 Hz, 1H), 4.11(m, 1H), 4.55(m, 1H),4.88(d, J=7.1 Hz, 1H), 6.69(d, J=7.8 Hz, 1H), 6.78(d, J=3.3 Hz, 1H),6.91(dd, J=5.1 Hz, 3.4 Hz, 1 H), 7.12(dd, J=5.2 Hz, 1.1 Hz, 1H)

TEST EXAMPLE Measurement of Inhibitory Activity against Calpain

Through the known method disclosed in Journal of Biological Chemistry,vol. 259, p.3210, (1984), m-calpain was purified from a brain of rat.The inhibitory activity against it was measured and determined accordingto the method disclosed in Journal of Biological Chemistry, vol. 259,p.12489 (1982). As a result, the 50% inhibitory concentration (IC₅₀) ofthe compound in Example 5 (Compound No. 257 in Table 2) was 10.1 μM.

What we claim is:
 1. An α-aminoketone derivative of the followingformula or a pharmaceutically acceptable salt thereof: ##STR934##wherein, R¹ is hydrogen, ##STR935## wherein R⁴ is a member selected fromthe group consisting of (a) C₁ to C₂₀ alkyl which is unsubstituted or issubstituted by at least one substituent selected from the groupconsisting of (1) C₃ to C₈ cycloalkyl, (2) C₆ to C₁₄ aryl which may besubstituted by C₁ to C₃ alkoxy or a halogen atom, (3) a 5 or 6 memberedheterocyclic group containing at least one hetero atom selected from thegroup consisting of nitrogen, sulfur and oxygen, (4) C₃ to C₁₅cycloalkyloxy, (5) C₆ to C₁₄ aryloxy which may be substituted by C₁ toC₃ alkoxy, halogen or trifluoromethyl, (6) C₇ to C₂₀ aralkyloxy and (7)C₆ to C₁₄ arylthio,(b) C₂ to C₁₀ alkenyl which is unsubstituted or issubstituted by C₆ to C₁₄ aryl which may be substituted by C₁ to C₃alkoxy or C₆ to C₁₄ aryl which may be substituted by C₁ to C₃ alkoxy,halogen, C₁ to C₃ alkyl or trifluoromethyl, (c) C₆ to C₁₄ aryl which isunsubstituted or is substituted by C₁ to C₃ alkoxy, halogen, C₁ to C₃alkyl or trifluoromethyl, and (d) a 5 or 6 membered heterocyclic groupcontaining at least one hetero atom selected from the group consistingof nitrogen, sulfur and oxygen,R² and R³ are independently hydrogen orC₁ to C₂₀ alkyl which is unsubstituted or is substituted by at least onemember selected from the group consisting of (a) C₃ to C₈ cycloalkyl,(b) C₆ to C₁₄ aryl which may be substituted by hydroxyl, C₁ to C₆ alkoxyor halogen, (c) C₁ to C₃ alkylthio, (d) hydroxyl, (e) C₁ to C₆ alkoxy,(f) C₇ to C₁₅ aralkyloxy, (g) C₂ to C₁₀ alkoxycarbonyl, (h) carboxyl,(i) amino, and (j) C₂ to C₈ alkanoylamino, ##STR936## is a 5 to 6membered heterocyclic group containing at least one hetero atom selectedfrom the group consisting of nitrogen, sulfur and oxygen whichheterocyclic group is unsubstituted or is substituted by halogen or C₁to C₃ alkyl, n is 0 or 1, and m is an integer of 1 to
 5. 2. A compoundaccording to claim 1 wherein R¹ is hydrogen, ##STR937## wherein R⁴ is C₁to C₁₀ alkyl which is unsubstituted or is substituted by at least onesubstituent selected from the group consisting of (1) C₃ to C₈cycloalkyl, (2) C₆ to C₁₄ aryl which may be substituted by C₁ to C₃alkoxy or halogen, (3) pyridyl, (4) C₆ to C₁₄ aryloxy which may besubstituted by C₁ to C₃ alkoxy, halogen or trifluoromethyl, (5) C₇ toC₁₅ aralkyloxy and (6) C₆ to C₁₄ arylthio, R² and R³ are independentlyC₁ to C₁₀ alkyl, and ##STR938## is furyl or thienyl.
 3. A compoundaccording to claim 1 wherein R¹ is hydrogen or ##STR939## wherein R⁴ isC₁ to C₁₀ alkyl which is unsubstituted or is substituted by C₆ to C₁₀aryl, R² and R³ are independently C₁ to C₁₀ alkyl, and ##STR940## isfuryl or thienyl.
 4. A pharmaceutical composition for the treatment ofdiseases resulting from abnormal sthenia of thiol protease whichcomprises an effective amount of a compound or salt thereof as definedin claim 1 and a pharmaceutically acceptable carrier therefor.
 5. Amethod for the treatment of a disease resulting from abnormal sthenia ofthiol protease which comprises administering to a patient in need ofsuch treatment an effective amount of a compound or salt thereof asdefined in claim 1.